Differences in tumor-associated T cell receptor repertoires between young-onset and average-onset colorectal cancer.

Authors

null

Stephanie Schmit

Cleveland Clinic, Cleveland, OH;

Stephanie Schmit , Ya-Yu Tsai , Kanika G. Nair , Shimoli V Barot , Shao Xiang , Suneel Deepak Kamath , Marilena Melas , Christopher P Walker , Raghvendra Srivastava , Timothy An-thy Chan , Joseph D. Bonner , Kevin McDonnell , Gregory Idos , Joel K Greenson , Hedy S Rennert , Gad Rennert , Stephen B. Gruber , Alok A. Khorana , David Liska

Organizations

Cleveland Clinic, Cleveland, OH; , 9500 Euclid Avenue, Cleveland, OH; , New York Genome Center, New York, NY; , City of Hope National Medical Center, Duarte, CA; , City of Hope National Comprehensive Cancer Center, Duarte, CA; , University of Michigan, Ann Arbor, MI; , CHS National Israeli Cancer Control Center, Haifa, Israel; , Clalit National Cancer Control Center, Haifa, Israel;

Research Funding

Other
Sondra and Stephen Hardis Chair for Oncology Research

Background: The incidence of colorectal cancer (CRC) among individuals younger than age 50 (young-onset CRC; YOCRC) has increased, yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. Some studies suggest that YOCRCs have more aggressive biology. Here, we compare tumor-associated T cell repertoires between patients with YOCRC and average-onset CRC (AOCRC). A robust, focused T cell response is a positive prognostic indicator; therefore, we hypothesized that YOCRCs demonstrate lower T cell abundance and greater T cell diversity than AOCRCs. Methods: The discovery cohort included 242 patients with histologically confirmed Stage I-IV CRC who underwent surgical resection at Cleveland Clinic from 2000 to 2020 and consented to a biorepository. YOCRC was defined as < 50 years at diagnosis (N = 126), and AOCRC as > 60 years (N = 116). DNA was extracted from frozen tumors, and T Cell Receptor (TCR) abundance and clonality were measured using immunoSEQ (Adaptive Biotechnologies). Following quality control, logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 YOCRC and 1,984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study with adjustment for sex, Jewish ethnicity, tumor location, and stage. Results: YOCRC patients were more likely to have left-sided tumors and be diagnosed at advanced stages in both cohorts. In the discovery cohort, YOCRC tumors had significantly lower TCR clonality (higher T cell diversity) compared to AOCRC tumors in a multivariable model adjusting for sex, race, tumor location and stage (OR: 0.38, 95% Confidence Interval (CI): 0.25-0.56, p < 0.0001). This association was also observed in the replication cohort (OR: 0.74, 95% CI: 0.62-0.89, p = 0.0013). In the replication cohort, further adjustment for microsatellite instability status did not substantially change the association (OR: 0.73, 95% CI: 0.61-0.88 p = 0.0012). When restricting to microsatellite stable tumors, clonality remained statistically significant in both the discovery and replication cohorts. No significant difference in TCR abundance was observed between YOCRC and AOCRC in either cohort. Conclusions: Higher T cell repertoire diversity, indicating a less focused intratumoral T cell response, is more frequently observed in YOCRC. Further studies are warranted to investigate the role of T cell diversity in the etiology and outcomes of YOCRC.

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Abstract Details

Meeting

2023 ASCO Gastrointestinal Cancers Symposium

Session Type

Poster Session

Session Title

Poster Session C: Cancers of the Colon, Rectum, and Anus

Track

Colorectal Cancer,Anal Cancer

Sub Track

Tumor Biology, Biomarkers, and Pathology

Citation

J Clin Oncol 41, 2023 (suppl 4; abstr 207)

DOI

10.1200/JCO.2023.41.4_suppl.207

Abstract #

207

Poster Bd #

L9

Abstract Disclosures

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